Blood borne myeloid cells (macrophages and dendritic cells) comprise a major component of the inflammatory infiltrates in patients with multiple sclerosis (MS) and animals with experimental autoimmune encephalomyelitis (EAE). They have been implicated in the demyelination and axonal loss that cause disability in these disorders. However, relatively little is known about how myeloid cells are regulated in the periphery and CNS during autoimmune demyelinating disease. We have found that myeloid progenitor cells are mobilized from the bone marrow at an accelerated rate immediately prior to EAE exacerbations. Newly exported Ly6ChiCD11b+ monocytes infiltrate the CNS during the preclinical stage and give rise to the CD11c+MHC ClassIIhi DC that constitute a significant percent of neuroinflammatory cells during the symptomatic stage.
In Aim 1 we will investigate the cytokine pathways and molecular mechanisms underlying the expansion and mobilization of bone marrow myeloid cells during EAE. Our working hypothesis is that GM-CSF and MIP-1a, induced by myelin-specific T cells, stimulate bone marrow stromal cells to produce G-CSF and CXCL1/2. These factors, in turn, activate resident neutrophils to secrete proteases that degrade chemokines and adhesion molecules critical for the sequestration of hematopoietic precursor cells in intramedullary niches. Interruption of any step in this pathway (ex, by neutralizing G-CSF or by inactivating proteases) will prevent myeloid cell release and ultimately exhaust the peripheral monocyte pools that provide a source of CNS infiltrating cells during relapses.
In Aim 2 we will investigate the factors that stimulate Ly6ChiCD11b+ monocytes to differentiate into CD11c+MHC Class IIhi DC within the CNS. We propose that CNS infiltrating monocytes acquire characteristics of myeloid dendritic cells consequent to direct interactions with myelin- specific T cells. The roles of candidate soluble factors (such as GM-CSF and TNF) and cell surface molecules (such as RANKL, CD40L and Lymphotoxin-?) will be assessed. Our studies are likely to provide insights into the pathways driving the mobilization and development of pathogenic myeloid cells during autoimmunity. The results are expected to suggest novel therapeutic targets and biomarkers in MS related to myeloid cell dysregulation.
Although recent advancements in the immunotherapy of multiple sclerosis (MS) have focused on the T cell component of the autoimmune response, myeloid cells (including macrophages and dendritic cells) compose the majority of CNS-infiltrating cells in MS and its model, experimental autoimmune encephalomyelitis (EAE), and mediate direct damage to neurons and glia. The purpose of this proposal is to elucidate the cytokine pathways and molecular mechanisms that underlie the mobilization of myeloid cells from the bone marrow and that drive their differentiation into pathogenic effector cells during autoimmune demyelinating disease. It is anticipated that our results will lead to the discovery of novel biomarkers and therapeutic targets related to myeloid cell dysregulation in MS.
| Giles, David A; Washnock-Schmid, Jesse M; Duncker, Patrick C et al. (2018) Myeloid cell plasticity in the evolution of central nervous system autoimmunity. Ann Neurol 83:131-141 |
| Segal, Benjamin M (2018) Enhancing natural killer cells is beneficial in multiple sclerosis - Commentary. Mult Scler :1352458518809296 |
| Stoolman, Joshua S; Duncker, Patrick C; Huber, Amanda K et al. (2018) An IFN?/CXCL2 regulatory pathway determines lesion localization during EAE. J Neuroinflammation 15:208 |
| Neal, Lori M; Xing, Enze; Xu, Jintao et al. (2017) CD4+ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis. MBio 8: |
| Grifka-Walk, Heather M; Segal, Benjamin M (2017) T-bet promotes the accumulation of encephalitogenic Th17 cells in the CNS. J Neuroimmunol 304:35-39 |
| Segal, Benjamin M; Giger, Roman J (2016) Stable biomarker for plastic microglia. Proc Natl Acad Sci U S A 113:3130-2 |
| Carbajal, Kevin S; Mironova, Yevgeniya; Ulrich-Lewis, Justin T et al. (2015) Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. J Immunol 195:2552-9 |
| Grifka-Walk, Heather M; Giles, David A; Segal, Benjamin M (2015) IL-12-polarized Th1 cells produce GM-CSF and induce EAE independent of IL-23. Eur J Immunol 45:2780-6 |
| Rumble, Julie M; Huber, Amanda K; Krishnamoorthy, Gurumoorthy et al. (2015) Neutrophil-related factors as biomarkers in EAE and MS. J Exp Med 212:23-35 |
| Baldwin, Katherine T; Carbajal, Kevin S; Segal, Benjamin M et al. (2015) Neuroinflammation triggered by ?-glucan/dectin-1 signaling enables CNS axon regeneration. Proc Natl Acad Sci U S A 112:2581-6 |
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